Primary synaptic circuits throughout most of the CNS, including the olfactory bulb, use amino acid transmitters including glutamate, GABA, and glycine. Despite progress in the characterization of these circuits, little is known about their modulation by endogenous neuroactive substances. Given the accepted roles of amino acid transmitters in synaptic plasticity and some forms of neuropathology it is possible that modulation of amino acid receptors by endogenous substances influences these processes. Thus, it is important to clarify mechanisms underlying such modulation. The transition metals, zinc and copper, represent endogenous neuroactive substances which are highly concentrated in the bulb. Because these transition metals have been shown to be released by neurons in other regions of the CNS, it has been proposed that they function as neuromodulators during synaptic transmission. In addition, the implication of zinc and/or copper in several neuropathologic conditions (Pick's disease, Wilson's disease, epilepsy, and Alzheimer's disease) suggests that these metals may be associated with abnormal modulation of synaptic pathways that use amino acid transmitters. This hypothesis is further supported by pilot data demonstrating modulation of amino acid-mediated currents by zinc and copper. Along with zinc and copper, the dipeptide carnosine also is found in the olfactory system. Although it has been proposed as a transmitter or modulator, attempts at verifying this hypothesis have produced equivocal results. However, the finding that olfactory sensory neurons contain zinc, carnosine, and glutamate, suggests the potential for a combined role in neuromodulation. Our pilot data suggesting that carnosine modulates the actions of zinc and copper on amino acid receptors on olfactory bulb neurons also are consistent with this possibility. The well-characterized circuits and rich supply of neuroactive substances make the mammalian olfactory bulb an ideal preparation for studying neuromodulation. Furthermore, olfactory dysfunction is an early manifestation of several neuropathologic conditions associated with aging (e.g. Parkinson's disease, Alzheimer's disease) that are thought to be linked to amino acid transmitter pathology. The goal of this proposal is to explore the modulatory actions of zinc, copper and carnosine on NMDA, GABAA and glycine receptors expressed by olfactory bulb neurons in primary culture, using electrophysiological techniques to focus on their role in synaptic transmission.